IMMEDIATE RELEASE FORMULATIONS OF d-LYSERGIC ACID DIETHYLAMIDE FOR THERAPEUTIC APPLICATIONS

ABSTRACT

A solid oral immediate release formulation of LSD, wherein the composition is produced by lyophilization of a feedstock in a pre-formed mold to form an orally disintegrating tablet. A method of making a solid oral immediate release formulation of LSD by lyophilizing a flash frozen stock solution of LSD and excipients, including a non-gelling matrix former, filler, and binder in a pre-formed mold, and forming an orally disintegrating tablet. A method of treating an individual by administering a solid oral immediate release formulation of LSD, wherein the composition is produced by lyophilization of a feedstock in a pre-formed mold to form an orally disintegrating tablet and treating the individual.

BACKGROUND OF THE INVENTION 1. Technical Field

The present invention relates to the formulation of drugs. Morespecifically, the present invention relates to an immediate releaseformulation for a pharmaceutical formulation of d-lysergic aciddiethylamide (LSD).

2. Background Art

Oral solution formulations are convenient for studies in a small numberof sites and with a limited number of patients, mainly early phasedevelopment studies, but may not be suitable for later phase developmentstudies run in many centers and across wide geographies nor forcommercialization due to challenges in product stability and supplychain, such as the potential requirement for cold chain storage.

Solid oral formulations as tablets or capsules are more common in laterphase clinical development and commercially due to advantages inproduction, supply chain, and patient convenience. Solid oralformulations can be immediate release, dissolving instantaneously in themouth or stomach, or extended release in which the drug release isprolonged over time.

Orally disintegrating tablets (ODTs) are another solid dosage form whichis formulated with the aim of increasing the dissolution rate of apharmaceutical product and promoting pre-gastric absorption. In order toachieve rapid disintegration rates, the ODT formulation must providehigh porosity, low density, and a low hardness (Berthoumieu et al.,2010; Bandari et al., 2008). This dosage form can be chosen to modifyabsorption or for patient populations that have difficulty in swallowing(Lindgren et al., 1993), and is also suitable for use in geriatric andpediatric patients, or for those who suffer from conditions such asdysphagia (Sastry et al., 2000).

From the perspectives of cost and simplicity, direct compression is acommon method for preparing ODTs. However, the disintegration capacityof ODTs produced in this way is limited by the size and hardness of theresulting tablets. An alternative method for preparing ODTs is freezedrying. For example, the Zydis® ODT (orally dissolving tablet)fast-dissolve formulation, is a freeze-dried oral solid dosage form thatdisperses almost instantly in the mouth with no water required.

LSD is derived from its German name LysergSaureDiethylamid (Lysergicacid diethylamide). Lysergide belongs to a family of indole alkylaminesthat includes numerous substituted tryptamines such as psilocin (theactive moiety of psilocybin) and N,N-dimethyltryptamine (DMT). The IUPACname for LSD is9,10-didehydro-N,N-diethyl-6-methylergoline-8β-carboxamide.

LSD can be used to assist psychotherapy for many indications includinganxiety, depression, addiction, personality disorder, and others and canalso be used to treat other disorders such as cluster headache,migraine, and others (Passie et al., 2008; Hintzen et al., 2010;Nichols, 2016; Liechti, 2017). Effects of LSD can include alteredthoughts, feelings, awareness of surroundings, dilated pupils, increasedblood pressure, and increased body temperature. Therapeutic use of LSDis showing promising results for treating various neurological andbehavioral disorders. However, due to its potency there can bechallenges in developing and manufacturing solid oral formulations ofLSD that meet pharmaceutically acceptable limits for content uniformityand chemical stability.

Clinical studies with LSD have focused on oral solution drug productforms. There has been little to no formulation development work withLSD. Oral solutions were used historically and almost all the oldstudies and anecdotal data are with oral solutions or impregnatedpapers/cartons.

There is a need for an LSD dosage form and drug product that is bothcommercially attractive to a broad patient population and meetsregulatory/quality expectations for suitability and robustness. Acommercially viable solid oral, immediate release pharmaceuticalformulation of d-Lysergic Acid Diethylamide (LSD), as a free base or ina salt form, does not currently exist as a marketed product or reportedin literature. With the expected therapeutic dose of LSD to be in the10's to 100's of micrograms, challenges exist for achieving acceptabledrug content uniformity and chemical stability. Furthermore, previousstudies have shown LSD in oral solution is not stable at roomtemperature (Holze et al 2019).

In addition to achieving a uniform and stable immediate release drugproduct formulation, the final drug product should be in a form that iseasily administered to a broad range of patient populations, including,but not limited to the elderly, pediatrics, and patients with acondition that may limit their ability to swallow.

SUMMARY OF THE INVENTION

The present invention provides a solid oral immediate releaseformulation of LSD, including LSD formulations intended for an orallydisintegrating tablet dosage form, wherein the composition is producedby lyophilization of a feedstock in a pre-formed mold to form an orallydisintegrating tablet.

The present invention further provides a method of making a solid oralimmediate release formulation of LSD by lyophilizing a flash frozenstock solution of LSD and excipients of a non-gelling matrix former,filler, binder, and buffer as well as additional excipients such asantioxidants, photostabilization agents, permeation enhancers andflavoring agents, in a pre-formed mold, and forming an orallydisintegrating tablet.

The present invention also provides for a method of treating anindividual by administering a solid oral immediate release formulationof LSD, wherein the composition is produced by lyophilization of afeedstock in a pre-formed mold to form an orally disintegrating tabletand treating the individual.

DESCRIPTION OF THE DRAWINGS

Other advantages of the present invention are readily appreciated as thesame becomes better understood by reference to the following detaileddescription when considered in connection with the accompanying drawingswherein:

FIG. 1 is a representation of D-LSD D-tartrate salt; and

FIG. 2 is a photograph of Zydis ODT containing LSD.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides for a formulation of LSD in a quick orimmediate release dosage form such as an orally disintegrating tablet.The term “quick release tablet” is a mechanism that (similar toimmediate-release dosage) delivers a drug immediately in contrast with adelay after its administration (delayed-release dosage) or for aprolonged period of time (extended-release (ER, XR, XL) dosage) or to aspecific target in the body (targeted-release dosage). Preferably, itrefers to minimal time dependent release in oral dose formulations. Thepresent invention provides a composition, preferably including LSD asits active, or one of its active ingredients, that dissolve relativelyquickly once orally ingested. This provides an easy to administer yetanticipated to be effective and efficacious therapeutic effect.

The LSD can be in a free base form or a salt form as a crystalline ornon-crystalline solid. The salt can be, but is not limited to,hydrochloride, hydrobromide, maleate, tartrate (including D-tartrate andmeso-tartrate), citrate, phosphate, fumarate, sulfate, mesylate,acetate, oxalate, benzoate, benzensulfonate, xinafoate, 1,5-Napthalenedisulfonate, ascorbate, and naphthalene-2-sulfonate. The dose of LSD canpreferably be 0.01-1 mg (10-1000 μg). However, dosing can be adjusteddepending on indication, age, weight, and other factors affecting thepharmacology, physiology, and drug/drug interactions in a given patient.

The preferred solid oral formulation is an orally disintegrating tablet(ODT) such as using ZYDIS® (Catalent, Inc.) technology, described inU.S. Pat. No. 9,192,580 B2, which is herein incorporated by reference.This is further shown in EXAMPLE 1. Typical ZYDIS® ODT formulationsinclude a non-gelling matrix former, filler, binder, and pH modifyingagent (i.e. buffer). In addition, antioxidants, photostabilizationagents, permeation enhancers, coloring agents, and sweeteners/flavoringagents can be included in ZYDIS® ODT formulations.

Examples of non-gelling matrix formers used include, but are not limitedto, non-gelling gelatin (including fish gelatin), maltodextrin, modifiedstarches, starch ethers, low molecular weight dextrans, and low tointermediate molecular weight cellulose gums (U.S. Pat. No. 10,548,839B2).

Examples of fillers used include lactose (including anhydrous),mannitol, dicalcium phosphate, calcium sulfate, starch (starch as usedherein can include dry or pre-gelled), cellulose (includingmicrocrystalline cellulose), kaolin, sodium chloride, sorbitol,trehalose, sucrose, etc.

Examples of binders include acacia gum, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, tragacanth, polyvinylpyrrolidone (PVP), starch, etc.

Buffer is added to target the formulation to a specific pH. Currently,three buffers, citrate, phosphate, and acetate, make up the majority ofbuffers used in parenteral pharmaceuticals approved by the FDA, but lessprecedented excipients are certainly available to use in commercialdosage forms. The pH of a formulation alternatively can be adjusted withunbuffered acid (i.e. hydrochloric acid) or unbuffered base (i.e. sodiumhydroxide).

Antioxidants can be added to the formulation in order to minimizedegradation due to oxidative stress. The term oxidation can be definedas the incorporation of oxygen into the structure of a drug, or as theprocess of converting one chemical substance into another derivativebearing a smaller number of electrons. Examples of such antioxidants areascorbic acid, citric acid, butylated hydroxy anisole (BHA), andbutylated hydroxyl toluene (BHT).

Many drugs are sensitive to light and therefore their formulatedproducts can degrade during manufacturing, storage, and administration.The photostability of a drug substance can be defined as the response ofthe drug or drug product to the exposure to solar, UV, and visible lightin the solid, semisolid, or liquid state that leads to a physical orchemical change. Undo light exposure can result in potency loss, alteredefficacy, and adverse biological effects. Various additives orencapsulation methods and compositions can be used to protect the activeproduct from light in order to minimize any degradation due to lightexposure (i.e. photostabilization agents).

Photo degradation can also occur in combination with oxygen exposure,resulting in photo-oxidation degradation. Some of the commonly usedantioxidants to protect against photo-oxidation are ascorbic acid,α-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), L-histidine, propyl gallate, and sulfur compounds. Ascorbic acid,α-tocopherol, β-carotene, and BHT act as free radical scavengers andsinglet oxygen quenchers and thus inhibit the photosensitizationreactions. If a drug substance acts as a photosensitizer and initiates achain reaction in the drug product, some of the excipients can beoxidized, while the drug can be protected from photodegradation.

The formulation can also contain permeability enhancers to increase theextent and/or rate of absorption. Examples of such enhancers aresulphoxides (such as dimethylsulphoxide, DMSO), azones (e.g.laurocapram), pyrrolidones (for example 2-pyrrolidone, 2P), alcohols andalkanols (ethanol, or decanol), glycols (for example propylene glycol,PG, a common excipient in topically applied dosage forms), surfactants(also common in dosage forms) and terpenes.

Coloring agents, sweeteners, and flavoring agents can also be added tosolid oral formulations in order to improve patient recognition andacceptability.

The compound of the present invention is administered and dosedconsidering the clinical condition of the individual patient, the siteand method of administration, scheduling of administration, patient age,sex, body weight and other factors known to medical practitioners. Thepharmaceutically “effective amount” for purposes herein is thusdetermined by such considerations as are known in the art. The amountmust be effective to achieve improvement including but not limited toimproved survival rate or more rapid recovery, or improvement orelimination of symptoms and other indicators as are selected asappropriate measures by those skilled in the art.

In the method of the present invention, the compound of the presentinvention can be administered in various ways. It should be noted thatit can be administered as the compound and can be administered alone oras an active ingredient in combination with pharmaceutically acceptablecarriers, diluents, adjuvants, and vehicles. The patient being treatedis a warm-blooded animal and, in particular, mammals including man. Thepharmaceutically acceptable carriers, diluents, adjuvants, and vehiclesgenerally refer to inert, non-toxic solid or liquid fillers, diluents orencapsulating material not reacting with the active ingredients of theinvention.

The doses can be single doses or multiple doses over a period of severaldays. The treatment generally has a length proportional to the length ofthe disease process and drug effectiveness and the patient species beingtreated.

Absorption of the active drug can be targeted. Drug absorption isdetermined by the drug's physicochemical properties, formulation, androute of administration. Dosage forms (e.g., tablets, capsules,solutions), consisting of the drug plus other ingredients, areformulated to be given by various routes (e.g., oral, buccal,sublingual, rectal, parenteral, topical, inhalational). Regardless ofthe route of administration, drugs must be in solution to be absorbed.Thus, solid forms (e.g., tablets, capsules) must be able to disintegrateand deaggregate. Solid oral tablets and capsule formulations typicallyhave gastric absorption, whereas an ODT formulation can be formulated totarget pre-gastric or buccal absorption which can further enhancebioavailability.

The present invention provides for a method of making a solid oralimmediate release formulation of LSD, as a free base or in a salt form,by lyophilizing a flash frozen stock solution of drug and excipients ina pre-formed mold to form an orally disintegrating tablet. This approachconsiders the challenges associated with formulating a low dose productwhile maintaining content uniformity and chemical integrity of LSD.

The present invention provides for a method of treating an individual,by administering a solid oral immediate release formulation of LSD,wherein the composition is produced by lyophilization of a feedstock ina pre-formed mold to form the orally disintegrating tablet and treatingthe individual.

The condition or disease being treated can include, but is not limitedto, anxiety disorders (including anxiety in advanced stage illness e.g.cancer, as well as generalized anxiety disorder), depression (includingpost partum depression, major depressive disorder andtreatment-resistant depression), headache disorder (including clusterheadaches and migraine headache), obsessive compulsive disorder (OCD),personality disorders (including conduct disorder), stress disorders(including adjustment disorders and post-traumatic stress disorder),drug disorders (including alcohol dependence or withdrawal, nicotinedependence or withdrawal, opioid dependence or withdrawal, cocainedependence or withdrawal, methamphetamine dependence or withdrawal),other addictions (including gambling disorder, eating disorder, and bodydysmorphic disorder), pain, neurodegenerative disorders (such asdementia, Alzheimer's Disease, Parkinson's Disease), autism spectrumdisorder, eating disorders, or neurological disorders (such as stroke).

The invention is further described in detail by reference to thefollowing experimental examples. These examples are provided for thepurpose of illustration only and are not intended to be limiting unlessotherwise specified. Thus, the invention should in no way be construedas being limited to the following examples, but rather, should beconstrued to encompass any and all variations which become evident as aresult of the teaching provided herein.

EXAMPLE 1 Lyophilization of d-LSD D-tartrate Stock Solution to Formulatean Orally Disintegrating Tablet

Solid oral formulations of d-LSD D-tartrate in a fast dispersing orallydisintegrating tablet (ODT) were produced the following method: A)Generating a formula stock solution containing d-LSD D-tartrate, anon-gelling matrix forming excipient, a filler excipient, and a bindingagent fully dissolved in water; B) Dosing the stock solution inpre-formed molds; and C) Lyophilizing the dosed formulations to removewater by sublimation. Formulation compositions are provided in TABLE 1.Images for Formulation 1 are shown in FIG. 2 . All formulationsdisintegrated in less than 60 seconds demonstrating immediate release.

TABLE 1 d-LSD D-tartrate formulations lyophilized to form orallydisintegrating tablets Component Formulation 1 Formulation 2 Formulation3 Approximate Wt % Drug d-LSD D-tartrate   <1% Non-gelling matrix FishGelatin Maltodextrin 2-10% Binder Methylcellulose  1-5% Filler MannitolMannitol Trehalose 2-10% Solvent Water qs to 100%

These formulations were protected from moisture ingress, set onstability at 40° C., and after one month tested for chemicaldegradation. The total chemical impurities are presented in TABLE 2.These results show minor changes in total impurities after one monthstored at accelerated conditions, demonstrating the suitability oflyophilized ODT formulations of d-LSD D-tartrate.

TABLE 2 Total Impurities of lyophilized d-LSD D-tartrate formulationsafter one month storage at 40° C. Time point Formulation 1 Formulation 2Formulation 3 T = 0 0.9 0.3 0.7 T = 1 mo @ 40° C. 1.6 0.2 0.5

Throughout this application, various publications, including UnitedStates patents, are referenced by author and year and patents by number.Full citations for the publications are listed below. The disclosures ofthese publications and patents in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

The invention has been described in an illustrative manner, and it is tobe understood that the terminology, which has been used is intended tobe in the nature of words of description rather than of limitation.

Obviously, many modifications and variations of the present inventionare possible in light of the above teachings. It is, therefore, to beunderstood that within the scope of the appended claims, the inventioncan be practiced otherwise than as specifically described.

What is claimed is:
 1. A composition of a solid oral immediate releaseformulation of LSD, comprising LSD contained within an immediate releasedosage form of an orally disintegrating tablet, wherein said compositionis produced by lyophilization of a feedstock in a pre-formed mold toform the orally disintegrating tablet.
 2. The composition of claim 1,further including a non-gelling matrix former chosen from the groupconsisting of non-gelling gelatin, maltodextrin, modified starches,starch ethers, low molecular weight dextrans, and low to intermediatemolecular weight cellulose gums.
 3. The composition of claim 1, furtherincluding a filler chosen from the group consisting of lactose,mannitol, dicalcium phosphate, calcium sulfate, starch, cellulose,kaolin, sodium chloride, sorbitol, trehalose, and sucrose.
 4. Thecomposition of claim 1, further including a binder chosen from the groupconsisting of acacia gum, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, tragacanth, polyvinylpyrrolidone (PVP), and starch.
 5. The composition of claim 1, furtherincluding a buffer chosen from the group consisting of citrate,phosphate, and acetate.
 6. The composition of claim 1, further includingan antioxidant chosen from the group consisting of ascorbic acid,butylated hydroxy anisole (BHA), and butylated hydroxyl toluene (BHT).7. The composition of claim 1, further including a photostabilizationagent.
 8. The composition of claim 1, further including a permeationenhancer chosen from the group consisting of sulphoxides, azones,pyrrolidones, alcohols, alkanols, glycols, surfactants, and terpenes. 9.The composition of claim 1, further including coloring agents,sweeteners, and flavoring agents.
 10. A method of making a solid oralimmediate release formulation of LSD, including the steps of:lyophilizing a flash frozen stock solution of LSD and excipients of anon-gelling matrix former, filler, binder, and buffer in a pre-formedmold; and forming an orally disintegrating tablet.
 11. The method ofclaim 10, wherein the non-gelling matrix former is chosen from the groupconsisting of non-gelling gelatin, maltodextrin, modified starches,starch ethers, low molecular weight dextrans, and low to intermediatemolecular weight cellulose gums.
 12. The method of claim 10, wherein thefiller is chosen from the group consisting of lactose, mannitol,dicalcium phosphate, calcium sulfate, starch, cellulose, kaolin, sodiumchloride, sorbitol, trehalose, and sucrose.
 13. The method of claim 10,wherein the binder is chosen from the group consisting of acacia gum,methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose,tragacanth, polyvinyl pyrrolidone (PVP), and starch.
 14. The method ofclaim 10, wherein the buffer is chosen from the group consisting ofcitrate, phosphate, and acetate.
 15. The method of claim 10, wherein theLSD is in a form chosen from free base and salt.
 16. The method of claim10, wherein the LSD is in a salt form and the salt is chosen from thegroup consisting of hydrochloride, hydrobromide, maleate, tartrate,citrate, phosphate, fumarate, sulfate, mesylate, acetate, and oxalate.17. A method of treating an individual, including the steps of:administering a solid oral immediate release formulation of LSD of anorally disintegrating tablet, wherein the composition is produced bylyophilization of a feedstock in a pre-formed mold to form the orallydisintegrating tablet; and treating the individual.
 18. The method ofclaim 17 wherein the individual has trouble swallowing, is elderly, orhas dementia.
 19. The method of claim 17, wherein said treating step isfurther defined as treating a condition or disease chosen from the groupconsisting of anxiety disorders, depression, headache disorder,obsessive compulsive disorder (OCD), personality disorders, stressdisorders, drug disorders, gambling disorder, eating disorder, bodydysmorphic disorder, pain, neurodegenerative disorders, autism spectrumdisorder, eating disorders, and neurological disorders.
 20. The methodof claim 17, wherein the LSD is in a form chosen from free base andsalt.
 21. The method of claim 17, wherein the LSD is in a salt form andthe salt is chosen from the group consisting of hydrochloride,hydrobromide, maleate, tartrate, citrate, phosphate, fumarate, sulfate,mesylate, acetate, and oxalate.
 22. The method of claim 17, wherein saidadministering step is further defined as administering 0.01-1 mg of LSD.